The six-layered mammalian neocortex derives from a pseudostratified neuroepithelium by a series of cell divisions of neuronal progenitors, neuroepithelial and radial glial cells. Neurogenesis, a major event in the developing neocortex, relies on the ability of radial glial cells (RGCs) to switch from proliferative self-expanding to differentiative neurongenerating/progenitor self-renewing divisions. However, the molecular mechanisms that control this switch in a correct temporal manner are not well understood. In this thesis, I demonstrated that the DOCK180 family member DOCK7, an activator of Rac GTPases, plays an important role in the regulation of RGC proliferation versus differentiation. Silencing of DOCK7 in RGCs of developing mouse embryos hampers neuronal differentiation and maintains cells as cycling progenitors. Conversely, DOCK7 overexpression promotes RGC differentiation into basal progenitors and neurons. Using different approaches, including live-cell imaging experiments, I obtained evidence that DOCK7 influences RGC fate and neurogenesis by controlling the apically directed interkinetic nuclear migration (INM) process of RGCs. Importantly, DOCK7 exerts its effects on INM and neurogenesis independently of its GEF activity towards Rac, but instead does so by antagonizing the microtubule growth-promoting function of the centrosome-associated protein TACC3. Taken together, DOCK7 interacts with TACC3 to control INM, as such governing RGC fate and genesis of neurons during cortical development.

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Sponsorship

Stony Brook University Libraries. SBU Graduate School in Department of Molecular and Cellular Biology. Charles Taber (Dean of Graduate School).